PROJECT SUMMARY Knee osteoarthritis (OA) is a common chronic painful disorder that is the most frequent cause of mobility disability in older people. The MOST study has been a major source of new knowledge about the course of this disease and factors that affect its course. Since the study began in 2003, it is increasingly recognized that by the time people develop chronic symptoms of knee OA, they usually have advanced structural findings of disease on MRI. Findings such as meniscal tears, malalignment and cartilage loss drive further structural deterioration and almost certainly limit prevention opportunities. We believe that prevention opportunities are likely to be greater if started in those who do not yet have severe continuous knee pain or advanced structural findings of disease. The functional impacts of knee OA occur in older people who experience multiple musculoskeletal comorbidities, and preventing disablement from OA requires a broader perspective than a focus on a single knee. For example, those with pain in one knee are at high risk of pain in other lower extremity musculoskeletal regions and, even if the knee is replaced, they may ultimately need treatment for pain in other joints developing as a consequence of the first joint affected. Also, in addition to functional loss, persons with OA experience buckling, falls and constraints in their involvement with the outside environment. We suggest there are opportunities to develop treatments and disease prevention strategies that have been unexplored and that by using new technologies and focusing on persons at a milder or earlier disease stage than previous studies, we can identify such opportunities. We propose to recruit a new mild disease cohort and continue to study the existing MOST cohort to identify new risk factors for disease and to study consequences of disease. Our goal is to find new strategies to prevent disease at an early stage and to limit the impact of disease once it has occurred.